Nalmefene for reduction of alcohol consumption in specific target populations

ABSTRACT

The present invention relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who has a high drinking risk level. The present invention also relates to nalmefene for use in the reduction of alcohol consumption in a patient with alcohol dependence who maintains a high DRL after an observation period following initial assessment.

FIELD OF THE INVENTION

The present invention relates to nalmefene for use in the reduction ofalcohol consumption in a patient with alcohol dependence who has a highdrinking risk level. The present invention also relates to nalmefene foruse in the reduction of alcohol consumption in a patient with alcoholdependence who maintains a high DRL after an observation periodfollowing initial assessment.

BACKGROUND OF THE INVENTION

Nalmefene[17-(cyclopropylmethyl)-4,5-alpha-epoxy-6-methylenemorphinan-3,14-diol]has the following general formula:

and can be prepared using methods that are well known in the art e.g.starting by manufacturing of naltrexone from noroxmorphone as describedin WO 2012/059103 and subsequently manufacturing nalmefene fromnaltrexone e.g. by the Wittig reaction as described in WO 2010/136039.The entire contents of each of WO 2012/059103 and WO 2010/136039 areincorporated herein by reference.

Nalmefene is a known opioid system modulator, with a distinct μ, δ, andκ receptor profile, which can inhibit pharmacological effects of bothadministered opioid agonists and endogenous agonists derived from theopioid system. The clinical usefulness of nalmefene comes from itsability to promptly and selectively reverse the effects of these opioidagonists.

Nalmefene has primarily been developed for use in the management ofalcohol dependence. A double-blind, placebo-controlled study has showngood effect of 20 to 80 mg daily oral dosing of nalmefene (Mason et al.,Arch. Gen. Psychiatry, (1999), Vol. 56: 719-724): while another studyreported no evidence of superiority of nalmetene over placebo in a studyevaluating 5, 20 and 40 mg daily doses of nalmefene (Anton et al., J.Clin. Psychopharmacol., (2004), Vol. 24(4): 421-428). A more recentstudy. showed good effect of nalmefene over placebo when a dose of 20 mgnalmefene was taken when the patient experienced a craving for alcohol(Karhuvaara et al., Alcohol Chin Exp. Res., (2007), Vol. 31 (7):1179-1187).

Based on independent evidence, high levels of alcohol consumption areassociated with an increased risk of health-related harm, as well asadverse social consequences. The World Health Organization (WHO) hasdefined drinking risk levels (DRLs) based on alcohol consumption inInternational Guide for Monitoring Alcohol Consumption and Related Harm.2000. World Health Organization, the entire contents of which areincorporated herein by reference. See Table 1.

TABLE 1 WHO Drinking Risk Levels (DRLs) of Alcohol Consumption TotalAlcohol Consumption (g/day) DRL Men Women Very high risk >100 >60 Highrisk >60 to 100 >40 to 60 Medium risk >40 to 60  >20 to 40 Low risk  1to 40   1 to 20

Risk levels according to Table 1 can be assessed e.g. by calculatingmean daily alcohol consumption in g/day over a month such as over 4weeks. There is a need for a new treatment for use in reduction ofalcohol consumption. Reduction of alcohol consumption is likely toprovide benefits associated with decreased risk of health-related harmand decreased number of adverse social consequences.

SUMMARY OF THE INVENTION

The present invention relates to a nalmefene for use in the reduction ofalcohol consumption in a patient with alcohol dependence, wherein saiduse comprises the following steps:

-   -   a) identifying a patient with alcohol dependence i) who has a        high DRL, and ii) who maintains a high DRL after an observation        period following initial assessment, and    -   b) administering a therapeutically effective amount of nalmefene        to the patient identified in step a), wherein said nalmefene is        to be administered as needed such as on each day the patient        perceives a risk of drinking alcohol, preferably 1-2 hours prior        to the anticipated time of drinking.

BRIEF DESCRIPTION OF DRAWINGS

FIGS. 1-12 show the change from baseline in monthly Heavy Drinking days(HDDs) and Total Alcohol Consumption (TAC) (g/day) per study. Resultsare shown for the Total study population, Patients with a high DRL atbaseline, Total study population excluding Early Reducers (ERs) andPatients with a high DRL at baseline and randomization

FIGS. 1 a-12 a show the change from baseline in monthly HDDs. X-axis:time (months); Y-axis: change in HDD.

FIGS. 1 b-12 b show the change from baseline in monthly TAC (g/day.X-axis: time (months); Y-axis: change in TAC (g/day).

(

=placebo,

=nalmefene, *=P-value<0.05). “B” denotes baseline, “R” denotesrandomization.

FIG. 1 a: Study 12014A, total study population, change in monthly HDD.

FIG. 1 b: Study 12014A, total study population, change in monthly TAC.

FIG. 2 a: Study 12014A, high DRL at baseline, change in monthly HDD.

FIG. 2 b: Study 12014A, high DRL at baseline, change in monthly TAC.

FIG. 3 a: Study 12014A, total study population excluding ERs, change inmonthly HDD.

FIG. 3 b: Study 12014A, total study population excluding ERs, change inmonthly TAC.

FIG. 4 a: Study 12014A, high DRL at baseline and randomization, changein monthly HDD.

FIG. 4 b: Study 12014A, high DRL at baseline and randomization, changein monthly TAC.

FIG. 5 a: Study 12023A, total study population, change in monthly HDD.

FIG. 5 b: Study 12023A, total study population, change in monthly TAC.

FIG. 6 a: Study 12023A, high DRL at baseline, change in monthly HDD.

FIG. 6 b: Study 12023A, high ORL at baseline, change in monthly TAC.

FIG. 7 a: Study 12023A, total study population excluding ERs, change inmonthly HDD.

FIG. 7 b: Study 12023A, total study population excluding ERs, change inmonthly TAC.

FIG. 8 a: Study 12023A, high ORL at baseline and randomization, changein monthly HDD.

FIG. 8 b: Study 12023A, high DRL at baseline and randomization, changein monthly TAC.

FIG. 9 a: Study 12013A, total study population, change in monthly HDD.

FIG. 9 b: Study 12013A, total study population, change in monthly TAC.

FIG. 10 a: Study 12013A, high DRL at baseline, change in monthly HDD.

FIG. 10 b: Study 12013A, high DRL at baseline, change in monthly TAC.

FIG. 11 a: Study 12013A, total study population excluding ERs, change inmonthly HDD.

FIG. 11 b: Study 12013A, total study population excluding ERs, change inmonthly TAC.

FIG. 12 a: Study 12013A, high DRL at baseline arid randomization, changein monthly HDD.

FIG. 12 b: Study 12013A, high DRL at baseline and randomization, changein monthly TAC.

DEFINITIONS

Throughout the description, the term “nalmefene” is intended to includeany forms of the compound, such as the free base and pharmaceuticallyacceptable salts. The free base and pharmaceutically acceptable saltsinclude anhydrous forms and solvated forms such as hydrates. Theanhydrous forms and the solvates include amorphous and crystallineforms. In a particular embodiment, nalmefene is in the form of thehydrochloride. In a more particular embodiment, nalmefene is in the formof the hydrochloride dihydrate. Throughout the application, when a doseis specified for nalmefene, said dose is calculated as the free base,i.e. when the nalmefene dose is 18 mg this corresponds to 18 mg ofnalmefene free base.

As used herein, the term “total alcohol consumption” abbreviated TAGindicates mean daily total alcohol consumption measured in g/day over amonth (=28 days).

As used herein, the term “heavy drinking day” abbreviated HDD indicatesa day with a total alcohol consumption ≧60 g of pure alcohol for men and≧40 g for women.

As used herein, “as-needed dosing” indicates that on each day a patientperceives a risk of drinking alcohol, one dose of nalmefene should betaken, preferably 1-2 hours prior to the anticipated time of drinking.If the patient has started drinking alcohol without taking nalmefene,the patient should take one dose as soon as possible after that.

As used herein, the term “drinking risk level” abbreviated DRL isdefined according to WHOs criteria according to Table 1 below.

TABLE 1 WHO Drinking Risk Levels (DRLs) of Alcohol Consumption TotalAlcohol Consumption (g/day) DRL Men Women Very high risk >100 >60 Highrisk >60 to 100 >40 to 60 Medium risk >40 to 60  >20 to 40 Low risk  1to 40   1 to 20

Drinking Risk Levels according to Table 1 can be assessed e.g. bycalculating mean daily alcohol consumption in g/day over a period suchas 1 week or longer, such as 2 weeks or longer, such as 3 weeks orlonger, such as 4 weeks or longer, such as 1 month or longer such as 2months or longer, such as 3 months or longer, such as 4 months orlonger, such as 5 months or longer, such as 6 months or longer, such asabout 1 year. Assessment of DRL can be performed by specialists and/orphysicians such as general practitioners and/or other health careproviders based on patients estimates of their alcohol consumption. Inthe three Lundbeck phase III studies described in the examples (12014A,12023A and 12013A) DRL was measured by assessment of mean daily alcoholconsumption in g/day over a 4 week period up to the initial visit. Aftera 1-2 week observation period the drinking risk level was re-assessed byassessment of mean daily alcohol consumption in g/day over said 1-2 weekobservation period.

Throughout the application, the term “high risk” or “at least high risk”is intended to include the two groups defined as “high risk” and “veryhigh risk” according to WHOs drinking risk levels listed in Table 1,i.e. patients having drinking risk level corresponding to a totalalcohol consumption of >60 g/day of pure alcohol for men and >40 g/dayfor women. The present invention does not distinguish between patientswith high and very high drinking risk levels, and when the terms “highdrinking risk level” or “high DRL” are used in a claim or in anembodiment of the invention it is intended to include both the groupdefined as “high risk” and the group defined as “very high risk”according to VVHOs drinking risk levels listed in Table 1.

As used herein, the term “early reducer” abbreviated ER indicates apatient included in the three Lundbeck phase Ill studies (12014A, 12023Aand 12013A) who had considerably reduced the alcohol consumption in theperiod between screening and randomisation. More specifically, patientsdefined as ERs have reduced their alcohol consumption from high ormedium DRL to a level below medium drinking risk level i.e. saidpatients had an alcohol consumption of 0-40 g/day for men and 0-20 g/dayfor women estimated as the mean daily alcohol consumption in a 1-2 weekperiod between screening and randomization.

As used herein, an “observation period in accordance with clinicalpractice” is an observation following initial assessment of the DRL.Said period is preferably 1-2 weeks most preferably about 2 weeks.

As used herein, the term “adult” indicates a person who is at least 16years old such as at least 18 years old.

As used herein, the term “adolescent” indicates a person who is 12-18years old such as 12-16 years old.

As used herein, the terms “motivational support” and “counseling focusedon enhanced treatment adherence and reduced alcohol consumption”indicate psychological motivation-enhancing interventions and can beused interchangeably with the terms “psychosocial support” or“psychosocial intervention focused on treatment adherence and reducingalcohol consumption”. Said motivational support can be administered by aspecialist and/or a physician such as a general practitioner and/orother health care providers. One example of such interventions is theBRENDA model, which is a time-limited, patient-centered clinicalmotivational intervention that complements the use of medication withfocus on changing behavior and increasing medication adherence. TheBRENDA model has been described by Starosta et al., J. Psychiatr. Pract.(2006), Vol. 12(2): 80-89, the entire contents of which are incorporatedherein by reference. The term “initial motivational support” indicatessuch motivation-enhancing interventions provided to the patient prior totreatment with nalmefene. The term “ongoing motivational support”indicates such motivation-enhancing interventions provided to thepatient concurrent to treatment with nalmefene e.g. on a recurrentbasis.

As used herein, “Pharmaceutical composition” refers to a dose such as anoral dose form, such as a solid oral dose form, typically tablets orcapsules. In a preferred embodiment, said dose form is suitable foras-needed dosing. Said pharmaceutical composition typically comprises atherapeutically effective amount of nalmefene and one or morepharmaceutically acceptable carrier. “Pharmaceutical compositions of thepresent invention” refers to all pharmaceutical compositions covered bythe claims and description.

As used herein, a “unit dosage form” refers to a formulation unit of apharmaceutical composition e.g. one tablet or capsule.

As used herein, “therapeutically effective amount” of a compound meansthe amount/dose of a compound or pharmaceutical composition that issufficient to produce an effective response (i.e., a biological ormedical response of a tissue, system, animal or human sought by aresearcher, veterinarian, medical doctor or other clinician) uponadministration to a patient. The “therapeutically effective amount” willvary depending on, inter alia, the disease and its severity, and on theage, weight, physical condition and responsiveness of the patient to betreated. Furthermore, the “therapeutically effective amount” may vary ifthe compound of the invention is combined with one or more compounds: Insuch a case the amount of a given compound might be lower, such as asub-effective amount. In one embodiment, a “therapeutically effectiveamount” of nalmefene is 18 mg.

As used herein, “treatment” and “treating” refers to the management andcare of a patient for the purpose of combating a condition, such as adisease or a disorder. The term is intended to include the full spectrumof treatments for a given condition from which the patient is suffering,such as administration of the active compound to alleviate the symptomsor complications, to delay the progression of the disease, disorder orcondition, to alleviate or relieve the symptoms and complications,and/or to cure or eliminate the disease, disorder or condition as wellas to prevent the condition, wherein prevention is to be understood asthe management and care of a patient for the purpose of combating thedisease, condition, or disorder and includes the administration of theactive compounds to prevent the onset of the symptoms or complications.

The term “alcohol dependence” is a commonly known term for a skilledperson and is defined in the revised 4^(th) edition of the Diagnosticand Statistical Manual of Mental Disorders (DSM-IV-TR) (Diagnostic andStatistical Manual of Mental Disorders, 4^(th) edition text revision,American Psychiatric Publishing, 2000), the entire contents of which areincorporated herein by reference. As used herein, the term “alcoholdependence” is defined as the presence of three or more of the sevenareas of life impairment related to alcohol in the same 12month period.These impairments include 1) tolerance, 2) withdrawal, 3) the alcohol isoften taken in larger amounts or over a longer period than was intended,4) persistent desire or unsuccessful efforts to cut down or controlalcohol intake, 5) a great deal of time is spent in activities necessaryto obtain alcohol, intake alcohol, or recover from its effects, 6)important social, occupational, or recreational activities are given upor reduced because of alcohol consumption, 7) alcohol use is continueddespite knowledge of having a persistent or recurrent physical orpsychological problem that is likely to have been caused or exacerbatedby alcohol consumption.

The term “alcohol use disorder” is defined in the 5^(th) edition of theDiagnostic and Statistical Manual of Mental Disorders (DSM-V)(Diagnostic and Statistical Manual of Mental Disorders, 5^(th) edition,American Psychiatric Publishing, 2013), the entire contents of which areincorporated herein by reference. As used herein, the term “alcohol usedisorder” is defined as a problematic pattern of alcohol use leading toclinically significant impairment or distress, as manifested by at leasttwo of the following, occurring within a 12-month period: 1) Alcohol isoften taken in larger amounts or over a longer period than was intended.2) There is a persistent desire or unsuccessful efforts to cut down orcontrol alcohol use. 3) A great deal of time is spent in activitiesnecessary to obtain alcohol, use alcohol, or recover from its effects.4) Craving, or a strong desire or urge to use alcohol. 5) Recurrentalcohol use resulting in a failure to fulfill major role obligations atwork, school, or home. 6) Continued alcohol use despite havingpersistent or recurrent social or interpersonal problems caused orexacerbated by the effects of alcohol. 7) Important social,occupational, or recreational activities are given up or reduced becauseof alcohol use. 8) Recurrent alcohol use in situations in which it isphysically hazardous. 9) Alcohol use is continued despite knowledge ofhaving a persistent or recurrent physical or psychological problem thatis likely to have been caused or exacerbated by alcohol. 10) Tolerance,as defined by either of the following: a) A need for markedly increasedamounts of alcohol to achieve intoxication or desired effect. b) Amarkedly diminished effect with continued use of the same amount ofalcohol. 11) Withdrawal, as manifested by either of the following: a)The characteristic withdrawal syndrome for alcohol (refer to Criteria Aand B of the criteria set for alcohol withdrawal). b) Alcohol (or aclosely related substance, such as a benzodiazepine) is taken to relieveor avoid withdrawal symptoms. “Alcohol use disorder” is separated intothe following three categories; Mild: Presence of 2-3 symptoms,Moderate: Presence of 4-5 symptoms, Severe: Presence of 6 or moresymptoms.

The term “Timeline Follow-back” (TLFB) is a method to obtain estimatesof daily drinking. Using memory aids, such as a calendar, patientsprovide retrospective estimates of the number of standard drinks foreach day. In the three Lundbeck phase III studies (12014A, 12023A and12013A) TLFB was characterized by the following approach. A day wasdefined as a 24-hour period starting at 6.00 a.m. and ending at 6.00a.m. the following morning. At the Screening Visit, each patient was toprovide a retrospective estimate of his/her daily drinking over theprevious month (a month was defined as a period of 28 consecutive days).At each subsequent visit, the patient was to provide information onhis/her drinking since the previous visit. If a patient missed a visit,the TLFB that was completed at the next visit was extended to cover thedays that should have been recorded at the missing visit. Patients coulduse their personal calendars to help them recalling their drinking orthey could use a calendar provided by the site for their personal use.Calendars were only to be used as a memory aid to support the patients'input to TLFB. The patients were asked to report their alcohol intake bystandard units according to the national definition of a standard unit.The standard national units were defined in standard drink conversioncards distributed to the patients.

“Hepatic impairment” can be assessed by the Child-Pugh scoring system,as defined in Child and Turcotte J G. Surgery and portal hypertension.In: The liver and portal hypertension. Edited by C G Child.Philadelphia: Saunders 1964:5064, the entire contents of which areincorporated herein by reference. Patients can be classified accordingto this system with e.g. “moderate or severe hepatic impairment”.

“Renal impairment” can be assessed by measuring estimated globalfiltration rate (eGFR) as described in Stevens et al., N. Engl. Med.(2006) 354:2473-2483, the entire contents of which are incorporatedherein by reference. Patients with “severe renal impairment” areclassified by an eGFR<30 ml/min Per. 1.73 m².

DETAILED DESCRIPTION OF THE INVENTION

The efficacy of nalmefene in the reduction of alcohol consumption inpatients with alcohol dependence (DSM-IV) has been evaluated in twoefficacy studies (Study 12014A and Study 12023A) and one safety study(Study 12013A) as described in the examples. All three studies wererandomized, double blind, parallel-group and placebo-controlled.

The studies included outpatients, aged ≧18 years, with a primarydiagnosis of alcohol dependence. A patient was eligible forparticipation in the study if, in the 4 weeks preceding the ScreeningVisit (Baseline period), he/she had >6 HDDs, at least a medium DRL(calculated as mean daily alcohol consumption in g/day i.e. >40 g/dayfor men and >20 g/day for women calculated as mean daily alcoholconsumption over the 4 week period preceding the screening visit), and≦14 consecutive abstinent days. The timeline followback (TLFB) methodwas used to obtain estimates of the patient's daily drinking.

At the initial visit (screening visit), the patients' clinical status,social situation, and alcohol consumption pattern were evaluated. Aftera 1- to 2-week observation period the drinking risk level wasre-assessed by calculating mean daily alcohol consumption in g/day overthe 1- to 2-week observation period, and treatment with nalmefene wasinitiated together with counseling with focus on motivating the patientsto adhere to the treatment and to change their drinking behavior.

The efficacy of nalmefene was measured using two co-primary endpoints:the change in the monthly number of heavy drinking days (HDDs) and thechange in the mean daily total alcohol consumption (TAC) per month (=28days). In the two 6 month efficacy studies and in the 12 month safetystudy, nalmefene was superior to placebo in reducing the number of HDDsand TAC at month 6 (see Table 6 and FIGS. 1, 5 and 9).

The inventors have found that in patients with a high DRL at baseline,i.e. alcohol consumption >60 g/day in men and >40 g/day in women atbaseline (based on mean daily alcohol consumption in g/day over a 4 weekperiod preceding the initial visit), the effect of nalmefene on HDDs andTAC was more pronounced compared to placebo than in the total populationi.e. nalmefene has a better effect in this patient group than in thetotal study population (see Table 6 and FIGS. 2, 6 and 10). Therefore inone aspect, the present invention relates to nalmefene for use in thereduction of alcohol consumption in a patient with alcohol dependencewho has a high drinking risk level i.e. a drinking risk levelcorresponding to >60 g/day of pure alcohol for men and >40 g/day forwomen. In one embodiment, the present invention relates to nalmefene foruse in the reduction of alcohol consumption in a patient with alcoholdependence who has at a least high drinking risk level according to WHOcriteria, such as a high or very high drinking risk level according toWHO criteria.

Furthermore, the inventors have observed that a sizeable proportion ofthe patients included in the three phase III studies (18%, 33% and 39%in studies 12014A, 12023A and 12013A, respectively) had considerablyreduced their alcohol consumption in the 1- to 2-week observation periodbetween screening and randomisation i.e. these patients had reducedtheir alcohol consumption from high or medium DRL to below medium DRL inthe 1- to 2-week observation period between screening and randomisation.These patients were characterized as Early Reducers (ERs). It was foundthat in the group of patients that were not ERs, the effect of nalmefeneon HDDs and TAC was more pronounced compared to placebo than in thetotal population i.e. nalmefene has a better effect in this group ofpatients than in the total study population (see Table 6 and FIGS. 3, 7and 11). Accordingly in another aspect the present invention relates tonalmefene for use in the reduction of alcohol consumption in a patientwith alcohol dependence who maintains the level of alcohol consumptionafter an observation period in accordance with clinical practice, suchas an observation period of 1-2 weeks. In one embodiment, the inventionrelates to nalmefene for use in the reduction of alcohol consumption ina patient with alcohol dependence who maintains at least medium DRLafter an observation period in accordance with clinical practice, suchas an observation period of 1-2 weeks.

It was found that in patients with a high DRL both at baseline and atrandomisation; i.e. patients who had a high DRL at baseline based onmean daily alcohol consumption in g/day over a 4 week period precedingthe initial visit and who maintained a high DRL in the 1- to 2-weekobservation period between screening and randomization; the effect ofnalmefene on HDDs and TAO was even further pronounced compared toplacebo than in the total population i.e. nalmefene has a particularlygood effect in this group of patients compared to its effect in thetotal study population (see Table 6 and FIGS. 4, 8 and 12). Accordingly,in one embodiment the present invention relates to nalmefene for use inthe reduction of alcohol consumption in a patient with alcoholdependence who have a high drinking risk level, i.e alcoholconsumption >60 g/day of pure alcohol for men and >40 g/day for women,and who continue to have a high drinking risk level after an observationperiod in accordance with clinical practice.

In one embodiment, patients according to the invention have a diagnosisof alcohol dependence according to the DSM-IV-TR criteria. In oneembodiment, patients according to the invention have a diagnosis ofalcohol use disorder according to the DSM-V criteria. In a furtherembodiment, patients according to the invention have a diagnosisselected from one or more of mild, moderate and severe alcohol usedisorder according to the DSM-V criteria. In one embodiment, saidpatients have mild alcohol use disorder. In one embodiment, saidpatients have moderate alcohol use disorder. In one embodiment, saidpatients have severe alcohol use disorder.

In a separate aspect, the present invention relates to a method forconducting a clinical study for assessment of the efficacy of atreatment on the reduction of alcohol consumption, wherein the methodcomprises the following steps;

-   -   a) screening patients based on their drinking risk level,    -   b) re-assessing the drinking risk level after an observation        period such as a 1- to 2-week observation period, such as a        2-week observation period,    -   c) excluding patients from the study who have considerably        reduced their alcohol consumption in the observation period of        step b).

In a further embodiment said patients selected for screening accordingto step a) have a primary diagnosis of DSM-IV alcohol dependence orDSM-V alcohol use disorder. In another further embodiment, said patientsexcluded in step c) have reduced their alcohol consumption to a drinkingrisk level from high or medium DRL to below medium ORL or from high ORLto below high DRL.

According to the present invention, nalmefene or a pharmaceuticallyacceptable salt thereof may be administered in any suitable way, e.g.orally or parenterally, and it may be presented in any suitable form forsuch administration, e.g. in the form of tablets, capsules, powders,syrups or solutions or dispersions for injection. In another embodiment,and in accordance with the purpose of the present invention, nalmefeneis administered in the form of a solid pharmaceutical entity, suitablyas a tablet or a capsule or in the form of a suspension, solution ordispersion for injection. Additionally, nalmefene may be administeredwith a pharmaceutically acceptable carrier, such as an adjuvant and/ordiluent.

Methods for the preparation of solid or liquid pharmaceuticalpreparations are well known in the art. See e.g. Remington: The Scienceand Practice of Pharmacy, 21^(st) ed., Lippincott Williams & Wilkins(2005). Tablets may thus be prepared by mixing the active ingredientswith an ordinary carrier, such as an adjuvant and/or diluent, andsubsequently compressing the mixture in a tabletting machine.Non-limiting examples of adjuvants and/or diluents include: corn starch,lactose, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvant or additive such as colorings, aroma, andpreservatives may also be used provided that they are compatible withthe active ingredients. The pharmaceutical compositions of the inventionthus typically comprise a therapeutically effective amount of nalmefeneand one or more pharmaceutically acceptable carrier. A suitable oralformulation of nalmefene is described in WO 2012/059103.

Without limiting the invention in any way, it is intended that any oneof the aspects or embodiments of this patent application is suitable forthe medicaments or pharmaceutical compositions described herein.

Nalmefene may be administered as an oral dose form, such as a solid oraldose form, typically tablets or capsules, or as a liquid oral dose form.Nalmefene may be administered in an immediate release dosage form or acontrolled or sustained release dosage form. Nalmefene may beconveniently administered orally in unit dosage forms, such as tabletsor capsules, containing the active ingredient in an amount from about 1to about 100 mg, such as from 5 to 50 mg. Typically, the pharmaceuticalcomposition comprises from 10 mg to 20 mg, such as about 10 mg, about 11mg, about 12 mg, about 13 mg, about 14 mg, about 15 Mg, about 16 mg,about 17 mg, about 18 mg, about 19 mg or about 20 mg of nalmefene. In apreferred embodiment, the pharmaceutical composition comprises about 18mg of nalmefene. In one embodiment, the unit dosage form comprisesnalmefene in a therapeutically effective amount.

In one embodiment, nalmefene is taken as-needed, that is, on each day apatient perceives a risk of drinking alcohol, one dose of nalmefeneshould be taken, preferably 1-2 hours prior to anticipated time ofdrinking. In one embodiment, if the patient has started drinking alcoholwithout taking nalmefene, the patient should take one dose of nalmefeneas soon as possible after that.

In one embodiment, nalmefene is in the form of the hydrochloridedihydrate.

Nalmefene according to the present invention is intended to be used fordosing in humans which are adults or adolescents. In one embodiment,nalmefene is intended to be used for dosing in humans 12 years or older,such as 14 years or older, such as 16 years or older, such as 18 yearsor older.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various “compounds” of the inventionor particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

It should be understood that the various aspects, embodiments,implementations and features of the invention mentioned herein may beclaimed separately, or in any combination.

EMBODIMENTS ACCORDING TO THE INVENTION

In the following, embodiments of the invention are disclosed. The firstembodiment is denoted E1, the second embodiment is denoted E2 and soforth.

E1. Nalmefene for use in the reduction of alcohol consumption in apatient with alcohol dependence who has a high DRL.

E2. Nalmefene according to embodiment 1, wherein said patient has a DRLcorresponding to consumption >60 g/day of pure alcohol for men and >40g/day for women.

E3. Nalmefene according to any of embodiments 1-2, wherein said DRL isassessed by calculating mean daily alcohol consumption in g/day over aperiod preceding assessment, wherein said period is 1 week or longer,such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks orlonger, such as 1 month or longer such as 2 months or longer, such as 3months or longer, such as 4 months or longer, such as 5 months orlonger, such as 6 months or longer such as about 1 year.

E4. Nalmefene according to any of embodiments 1-3, wherein said patienthas been identified as having a high DRL.

E5. Nalmefene according to any of embodiments 1-4, wherein said patientcontinues to have a high DRL despite initial motivational support.

E6. Nalmefene according to any of embodiments 1-4, wherein said patientmaintains a high DRL after an observation period in accordance with calpractice such as an observation period of 1-2 weeks, such as anobservation period of about 2 weeks.

E7. Nalmefene according to any of embodiments 1-5, wherein said patientmaintains a high DRL after an observation period of 1-2 weeks followinginitial assessment of the DRL such as after an observation period ofabout 2 weeks following initial assessment of the DRL.

E8. Nalmefene according to any of embodiments 5-7, wherein saidmaintained high DRL is assessed by calculating mean daily alcoholconsumption in g/day over said observation period.

E9. Nalmefene according to any of embodiments 5-8, wherein saidmaintained DRL corresponds to consumption >60 g/day of pure alcohol formen and >40 g/day for women.

E10. Nalmefene for use in the reduction of alcohol consumption in apatient with alcohol dependence who maintains the level of alcoholconsumption despite initial motivational support.

E11. Nalmefene for use in the reduction of alcohol consumption in apatient who maintains the level of alcohol consumption after anobservation period in accordance with clinical practice such as anobservation period of 1-2 weeks, such as an observation period of about2 weeks.

E12. Nalmefene for use in the reduction of alcohol consumption in apatient with alcohol dependence who maintains at least medium DRL afteran observation period following initial assessment such as anobservation period of 1-2 weeks, such as an observation period of about2 weeks.

E13. Nalmefene according to embodiments 10-12, wherein said maintainedDRL corresponds to consumption >40 g/day of pure alcohol for men and >20g/day for women.

E14. Nalmefene according to any of embodiments 10-13, wherein saidpatient has a high DRL at initial assessment.

E15. Nalmefene according to embodiment 14, wherein said patient has aDRL corresponding to consumption >60 g/day of pure alcohol for menand >40 g/day for women at initial assessment.

E16. Nalmefene according to any of embodiments 14-15, wherein saidpatient maintains a high DRL after said observation period.

E17. Nalmefene according to any of embodiments 10-16, wherein saidmaintained DRL is assessed by calculating mean daily alcohol consumptionin g/day over said observation period.

E18. Nalmefene according to any of embodiments 14-17, wherein said highDRL at initial assessment is assessed by calculating mean daily alcoholconsumption in g/day over a period preceding assessment, wherein saidperiod is 1 week or longer, such as 2 weeks or longer, such as 3 weeksor longer, such as 4 weeks or longer, such as 1 month or longer such as2 months or longer, such as 3 months or longer, such as 4 months orlonger, such as 5 months or longer, such as 6 months or longer, such asabout 1 year.

E19. Nalmefene according to any of embodiments 14-18, wherein saidpatient has been identified as having a high DRL.

E20. Nalmefene for use in reduction of alcohol consumption in a patientwith alcohol dependence who has a DRL corresponding to consumption >60g/day of pure alcohol for men and >40 g/day for women assessed bycalculating mean daily alcohol consumption in g/day over a periodpreceding assessment; wherein said patient maintains a DRL correspondingto consumption >60 g/day of pure alcohol for men and >40 g/day for womenafter an observation period following initial assessment, assessed bycalculating mean daily alcohol consumption in g/day over saidobservation period.

E21. Nalmefene according to embodiment 20, wherein said period precedingassessment is 1 week or longer, such as 2 weeks or longer, such as 3weeks or longer, such as 4 weeks or longer, such as 1 month or longersuch as 2 months or longer, such as 3 months or longer, such as 4 monthsor longer, such as 5 months or longer, such as 6 months or longer, suchas about 1 year.

E22. Nalmefene according to any of embodiments 20-21, wherein saidobservation period following initial assessment is 1-2 weeks such asabout 2 weeks.

E23. Nalmefene according to any of embodiments 1-22, wherein saidnalmefene is to be used as-needed, such as on each day the patientperceives a risk of drinking alcohol, preferably 1-2 hours prior to theanticipated time of drinking.

E24. Nalmefene for use in reduction of alcohol consumption in a patientwith alcohol dependence, wherein said use comprises the following steps;

-   -   a) identifying a patient with alcohol dependence i) who has a        high DRL, and/or ii) who maintains the DRL of alcohol        consumption after an observation period following initial        assessment, and    -   b) administering nalmefene to the patient identified in step a),        wherein said nalmefene is to be administered as-needed, such as        on each day the patient perceives a risk of drinking alcohol,        preferably 1-2 hours prior to the anticipated time of drinking.

E25. Nalmefene according to embodiment 24, wherein said observationperiod following initial assessment is 1-2 weeks, such as about 2 weeks.

E26. Nalmefene according to any of embodiments 21-25, wherein saidpatient identified in step a) has a DRL corresponding to consumption >60g/day of pure alcohol for men and >40 g/day for women.

E27. Nalmefene according to any of embodiments 24-26, wherein said highDRL identified in step a) i) has been assessed by calculating mean dailyalcohol consumption in g/day over a period preceding assessment, whereinsaid period of 1 week or longer, such as 2 weeks or longer, such as 3weeks or longer. such as 4 weeks or longer, such as 1 month or longersuch as 2 months or longer, such as 3 months or longer, such as 4 monthsor longer, such as 5 months or longer, such as 6 months or longer, suchas about 1 year.

E28. Nalmefene according to any of embodiments 24-27, wherein saidmaintained DRL in step a) ii) is assessed by calculating mean dailyalcohol consumption in g/day over said observation period.

E29. Nalmefene according to any of embodiments 1-28, wherein saidpatient does not require immediate detoxification and/or wherein saidpatient does not have physical withdrawal symptoms.

E30. Nalmefene according to any of embodiments 1-29, wherein saidpatient is subject to ongoing motivational support.

E31. Nalmefene according to any of embodiments 1-30, wherein saidpatient is subject to counseling focused on enhanced treatment adherenceand reduced alcohol consumption.

E32. Nalmefene according to embodiment 31, wherein said counseling isperformed according to the BRENDA model.

E33. Nalmefene according to any of embodiments 1-32, wherein saidpatient is a patient for whom immediate abstinence is not a treatmentgoal.

E34. Nalmefene according to any of embodiments 1-33, wherein saidnalmefene is to be used for a treatment period of 6 -12 months, such as6 months.

E35. Nalmefene according to any of embodiments 1-34, wherein saidpatient is an adult or an adolescent.

E36. Nalmefene according to any of embodiments 1-35, wherein saidpatient is 12 years or older, such as 14 years or older, such as 16years or older, such as 18 years or older.

E37. Nalmefene according to any of embodiments 1-36, wherein saidnalmefene is used in a dose of 10-20 mg such as 10 mg, 11 mg, 12 mg, 13mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg.

E38. Nalmefene according to embodiment 37, wherein said nalmefene isused in a dose of 18 mg.

E39. Nalmefene according to any of embodiments 1-38, wherein saidnalmefene is used in the form of a pharmaceutically acceptable acidaddition salt.

E40. Nalmefene according to embodiment 39, wherein said nalmefene isused in the form of the hydrochloride salt.

E41. Nalmefene according to embodiment 40, wherein said nalmefene isused in the form of the hydrochloride dihydrate.

E42. Nalmefene according to any of embodiments 1-41, wherein saidnalmefene is used in a crystalline form.

E43. Nalmefene according to any of embodiments 1-42, wherein saidnalmefene is used in an oral dose form such as tablets or capsules.

E44. Nalmefene according to any of embodiments 1-43, wherein saidnalmefene is used in combination with a further active ingredient.

E45. Nalmefene according to any of embodiments 1-44, wherein saidpatient does not fall into one or more of the following categories:patients taking opioid analgesics, opioid-addicted patients withoutsuccessful withdrawal, patients with acute symptoms of opioidwithdrawal, patients for whom re cent use of opioids is suspected,patients with moderate or severe hepatic impairment, patients withmoderate or severe renal impairment, patients with current or recentopioid addiction, patients with a recent history of acute alcoholwithdrawal syndrome (including hallucinations, seizures, and deliriumtremens).

E46. A method for reduction of alcohol consumption in a patient withalcohol dependence who has a high DRL, which method comprises theadministration of a therapeutically effective amount of nalmefene tosaid patient.

E47. The method according to embodiment 46, wherein said patient has aDRL corresponding to consumption >50 g/day of pure alcohol for menand >40 g/day for women.

E48. The method according to any of embodiments 46-47, wherein said DRLis assessed by calculating mean daily alcohol consumption in g/day overa period preceding assessment, wherein said period is 1 week or longer,such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks orlonger, such as 1 month or longer such as 2 months or longer, such as 3months or longer, such as 4 months or longer, such as 5 months orlonger, such as 6 months or longer, such as about 1 year.

E49. The method according to any of embodiments 46-48, wherein saidpatient has been identified as having a high DRL.

E50. The method according to any of embodiments 46-49, wherein saidpatient continues to have a high DRL despite initial motivationalsupport.

E51. The method according to any of embodiments 46-50, wherein saidpatient maintains a high DRL after an observation period in accordancewith clinical practice such as an observation period of 1-2 weeks suchas an observation period of about 2 weeks.

E52. The method according to any of embodiments 46-50, wherein saidpatient maintains a high DRL after an observation period of least 1 weekfollowing initial assessment of the DRL such as after an observationperiod of about 2 weeks following initial assessment of the DRL.

E53. The method according to any of embodiments 50-52, wherein saidmaintained high DRL is assessed by calculating mean daily alcoholconsumption in g/day over said observation period.

E54. The method according to any of embodiments 50-53, wherein saidmaintained DRL corresponds to consumption >60 g/day of pure alcohol formen and >40 g/day for women.

E55. A method for reduction of alcohol consumption in a patient withalcohol dependence who maintains the level of alcohol consumptiondespite initial motivational support, which method comprises theadministration of a therapeutically effective amount of nalmefene tosaid patient.

E56. A method for reduction of alcohol consumption in a patient withalcohol dependence who maintains the level of alcohol consumption afteran observation period in accordance with clinical practice such as anobservation period of 1-2 weeks such as an observation period of about 2weeks, which method comprises the administration of a therapeuticallyeffective amount of nalmefene to said patient.

E57. A method for reduction of alcohol consumption in a patient withalcohol dependence who maintains at least medium DRL after anobservation period following initial assessment such as an observationperiod of 1-2 weeks, such as an observation period of about 2 weeks,which method comprises the administration of a therapeutically effectiveamount of nalmefene to said patient.

E58. The method according to embodiments 55-57, wherein said maintainedDRL corresponds to consumption >40 g/day of pure alcohol for men and >20g/day for women.

E59. The method to any of embodiments 55-58, wherein said patient has ahigh DRL at initial assessment.

E60. The method according to embodiment 59, wherein said patient has aDRL corresponding to consumption >60 g/day of pure alcohol for menand >40 g/day for women at initial assessment.

E61. The method according to any of embodiments 55-60, wherein saidpatient maintains a high DRL after said observation period.

E62. The method according to any of embodiments 55-61, wherein saidmaintained DRL is assessed by calculating mean daily alcohol consumptionin g/day over said observation period.

E63. The method according to any of embodiments 59-62, wherein said highDRL at initial assessment is assessed by calculating mean daily alcoholconsumption in g/day over a period preceding assessment, wherein saidperiod is 1 week or longer, such as 2 weeks or longer such as 3 weeks orlonger, such as 4 weeks or longer, such as 1 month or longer such as 2months or longer, such as 3 months or longer, such as 4 months orlonger, such as 5 months or longer, such as 6 months or longer, such asabout 1 year.

E64. The method according to any of embodiments 59-63, where saidpatient has been identified as having a high DRL.

E65. A method for reduction of alcohol consumption in a patient withalcohol dependence who has a DRL corresponding to consumption >60 g/dayof pure alcohol for men and >40 g/day for women assessed by calculatingmean dairy alcohol consumption in g/day over a period precedingassessment, wherein said patient maintains a DRL corresponding toconsumption >60 g/day of pure alcohol for men and >40 g/day for womenafter an observation following initial assessment, assessed bycalculating mean daily alcohol consumption in g/day over saidobservation period, which method comprises the administration of atherapeutically effective amount of nalmefene to said patient.

E66. The method according to embodiment 65, wherein said periodpreceding assessment is 1 week or longer, such as 2 weeks or longer,such as 3 weeks or longer, such as 4 weeks or longer, such as 1 month orlonger such as 2 months or longer, such as 3 months or longer, such as 4months or longer, such as 5 months or longer, such as 6 months orlonger, such as about 1 year.

E67. The method according to any of embodiments 65-66, wherein saidobservation period in following initial assessment is 1-2 weeks such asabout 2 weeks.

E68. The method according to any of embodiments 46-67, wherein saidnalmefene is administered as-needed, such as on each day the patientperceives a risk of drinking alcohol, preferably 1-2 hours prior to theanticipated time of drinking.

E69. A method for reduction of alcohol consumption in a patient withalcohol dependence, wherein said method comprises the following steps;

-   -   a) identifying a patient with alcohol dependence i) who has a        high DRL, and/or ii) who maintains the DRL of alcohol        consumption after an observation period following initial        assessment, and    -   b) administering a therapeutically effective amount of nalmefene        to the patient identified in step a), wherein said nalmefene is        to be administered as-needed, such as on each day the patient        perceives a risk of drinking alcohol, preferably 1-2 hours prior        to the anticipated time of drinking.

E70. The method according to embodiment 69. wherein said observationperiod following initial assessment is 1-2 weeks, such as about 2 weeks.

E71. The method according to any of embodiments 69-70, wherein thepatient identified in step a) has a DRL corresponding to consumption >60g/day of pure alcohol for men and >40 g/day for women.

E72. The method according to any of embodiments 69-71, wherein said highDRL identified in step a) i) has been assessed by calculating mean dailyalcohol consumption in g/day over a period preceding assessment, whereinsaid period is 1 week or longer, such as 2 weeks or longer, such as 3weeks or longer, such as 4 weeks or longer, such as 1 month or longersuch as 2 months or longer, such as 3 months or longer, such as 4 monthsor longer, such as 5 months or longer, such as 6 months or longer, suchas about 1 year.

E73. The method according to any of embodiments 69-72, wherein saidmaintained DRL in step a) ii) is assessed by calculating mean dailyalcohol consumption in g/day over said observation period.

E74. The method according to any of embodiments 46-73, wherein saidpatient does not require immediate detoxification and/or wherein saidpatient does not have physical withdrawal symptoms.

E75. The method according to any of embodiments 46-74, wherein saidpatient is subject to ongoing motivational support.

E76. The method according to any of embodiments 46-76, wherein saidpatient is subject to counseling focused on enhanced treatment adherenceand reduced alcohol consumption.

E77. The method according to embodiment 76, wherein said counseling isperformed according to the BRENDA model.

E78. The method according to any of embodiments 46-77, wherein saidpatient is a patient for whom immediate abstinence is not a treatmentgoal.

E79. The method according to any of embodiments 46-78, wherein saidnalmefene is to be used for a treatment period of 6 -12 months, such as6 months.

E80. The method according to any of embodiments 46-79, wherein saidpatient is an adult or an adolescent.

E81. The method according to any of embodiments 46-80, wherein saidpatient is 12 years or older, such as 14 years or older, such as 16years or older, such as 18 years or older.

E82. The method according to any of embodiments 46-81, wherein theamount of nalmefene is 10-20 mg such as 10 mg, 11 mg, 12 mg, 13 mg, 14mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg.

E83. The method according to embodiment 82, wherein the amount ofnalmefene is 18 mg.

E84. The method according to any of embodiments 46-83, wherein saidnalmefene is administered in the form of a pharmaceutically acceptableacid addition salt.

E85. The method according to embodiment 84, wherein said nalmefene isadministered in the form of the hydrochloride salt.

E86. The method according to embodiment 85, wherein said nalmefene isadministered in the form of the hydrochloride dihydrate.

E87. The method according to any of embodiments 46-86, wherein saidnalmefene is administered in a crystalline form.

E88. The method according to any of embodiments 46-87, wherein saidnalmefene is administered in an oral dose form such as tablets orcapsules.

E89. The method according to any of embodiments 46-88, wherein saidnalmefene is administered in combination with a further activeingredient.

E90. The method according to any of embodiments 46-89, wherein saidpatient does not fall into one or more of the following categories:patients taking opioid analgesics, opioid-addicted patients withoutsuccessful withdrawal, patients with acute symptoms of opioidwithdrawal, patients for whom recent use of opioids is suspected,patients with moderate or severe hepatic impairment, patients withmoderate or severe renal impairment, patients with current or recentopioid addiction, patients with a recent history of acute alcoholwithdrawal syndrome (including hallucinations, seizures, and deliriumtremens).

E91. Use of nalmefene for the manufacture of a medicament for reductionof alcohol consumption in a patient with alcohol dependence who has ahigh DRL.

E92. The use according to embodiment 91, wherein said patient has a DRLcorresponding to consumption >60 g/day of pure alcohol for men and >40g/day for women.

E93. The use according to any of embodiments 91-92, wherein said DRL isassessed by calculating mean daily alcohol consumption in g/day over aperiod preceding assessment, wherein said period is 1 week or longer,such as 2 weeks or longer, such as 3 weeks or longer, such as 4 weeks orlonger, such as 1 month or longer such as 2 months or longer, such as 3months or longer, such as 4 months or longer, such as 5 months orlonger, such as 6 months or longer, such as about 1 year.

E94. The use according to any of embodiments 91-93, wherein said patienthas been identified as having a high DRL.

E95. The use according to any of embodiments 91-94, wherein said patientcontinues to have a high DRL despite initial motivational support.

E96. The use according to any of embodiments 91-95, wherein said patientmaintains a high DRL after an observation period in accordance withclinical practice such as an observation period of 1-2 weeks such as anobservation period of about 2 weeks.

E97. The use according to any of embodiments 91-95, wherein said patientmaintains a high DRL after an observation period of 1-2 weeks followinginitial assessment of the DRL such as after an observation period ofabout 2 weeks following initial assessment of the DRL.

E98. The use according to any of embodiments 95-97, wherein saidmaintained high DRL is assessed by calculating mean daily alcoholconsumption in g/day over said observation period.

E99. The use according to any of embodiments 95-98, wherein saidmaintained DRL corresponds to consumption >60 g/day of pure alcohol formen and >40 g/day for women.

E100. Use of nalmefene for the manufacture of a medicament for reductionof alcohol consumption in a patient with alcohol dependence whomaintains the level of alcohol consumption despite initial motivationalsupport.

E101. Use of nalmefene for the manufacture of a medicament for reductionof alcohol consumption in a patient who maintains the level of alcoholconsumption after an observation period in accordance with clinicalpractice such as an observation period of 1-2 weeks, such as anobservation period of about 2 weeks.

E102. Use of nalmefene for the manufacture of a medicament for reductionof alcohol consumption in a patient with alcohol dependence whomaintains at least medium DRL after an observation period followinginitial assessment such as an observation period of 1-2 weeks, such asan observation period of 2 weeks.

E103. The use according to any of embodiments 100-102, wherein saidmaintained DRL corresponds to consumption >40 g/day of pure alcohol formen and >20 g/day for women.

E104. The use according to any of embodiments 100-103, wherein saidpatient has a high DRL at initial assessment.

E105. The use according to embodiment 104, wherein said patient has aDRL corresponding to consumption >60 g/day of pure alcohol for menand >40 g/day for women at initial assessment.

E106. He use according to any of embodiments 101-105, wherein saidpatient maintains a high DRL after said observation period.

E107. The use according to any of embodiments 101-106, wherein saidmaintained DRL is assessed by calculating mean daily alcohol consumptionin g/day over said observation period.

E108. The use according to any of embodiments 104-107, wherein said highDRL at initial assessment is assessed by calculating mean daily alcoholconsumption in g/day over a period preceding assessment, wherein saidperiod is 1 week or longer, such as 2 weeks or longer, such as 3 weeksor longer, such as 4 weeks or longer, such as 1 month or longer such as2 months or longer, such as 3 months or longer, such as 4 months orlonger, such as 5 months or longer, such as 6 months or longer, such asabout 1 year.

E109. The use according to any of embodiments 104-108, wherein saidpatient has been identified as having a high DRL.

E110. Use of nalmefene for the manufacture of a medicament for reductionof alcohol consumption in a patient with alcohol dependence who has aDRL corresponding to consumption >60 g/day of pure alcohol for menand >40 g/day for women assessed by calculating mean daily alcoholconsumption in g/day over a preceding assessment, wherein said patientmaintains a DRL corresponding to consumption >60 g/day of pure alcoholfor men and >40 g/day for women after an observation period followinginitial assessment, assessed by calculating mean daily alcoholconsumption in g/day over said observation period.

E111. The use according to embodiment 110, wherein said period precedingassessment is 1 week or longer, such as 2 weeks or longer, such as 3weeks or longer, such as 4 weeks or longer, such as 1 month or longersuch as 2 months or longer, such as 3 months or longer, such as 4 monthsor longer, such as 5 months or longer, such as 6 months or longer, suchas about 1 year.

E112. The use according to any of embodiments 110-111, wherein saidobservation period following initial assessment is 1-2 weeks such asabout 2 weeks.

E113. The use according to any of embodiments 91-112. wherein saidmedicament is to be taken as-needed, such as on each day the patientperceives a risk of drinking alcohol, preferably 1-2 hours prior to theanticipated time of drinking.

E114. Use of nalmefene for the manufacture of a medicament for reductionof alcohol consumption in a patient with alcohol dependence, whereinsaid use comprises the following steps;

-   -   a) manufacturing a medicament comprising nalmefene,    -   b) identifying a patient with alcohol dependence i) who has a        high DRL, and/or ii) who maintains the DRL of alcohol        consumption after an observation period following initial        assessment, and    -   c) administering said medicament to the patient identified in        step b). wherein said medicament is to be administered        as-needed, such as on each day the patient perceives a risk of        drinking alcohol, preferably 1-2 hours prior to the anticipated        time of drinking.

E115. The use according to embodiment 114, wherein said observationperiod following initial assessment is 1-2 weeks, such as 2 weeks.

E116. The use according to any of embodiments 114-115, wherein saidpatient identified in step b) has a DRL corresponding to consumption >60g/day of pure alcohol for men and >40 g/day for women.

E117. The use according to any of embodiments 114-116, wherein said highDRL in identified in step b) i) has been assessed by calculating meandaily alcohol consumption in g/day over a period preceding assessment,wherein said period is 1 week or longer, such as 2 weeks or longer, suchas 3 weeks or longer, such as 4 weeks or longer, such as 1 month orlonger such as 2 months or longer, such as 3 months or longer, such as 4months or longer, such as 5 months or longer, such as 6 months orlonger, such as about 1 year.

E118. Nalmefene according to any of embodiments 114-117, wherein saidmaintained DRL in step b) ii) is assessed by calculating mean dailyalcohol consumption in g/day over said observation period.

E119. The use according to any of embodiments 91-118, wherein saidpatient does not require immediate detoxification and/or wherein saidpatient does not have physical withdrawal symptoms.

E120. The use according to any of embodiments 91-119, wherein saidpatient is subject to ongoing motivational support.

E121. The use according to any of embodiments 91-120, wherein saidpatient is subject to counseling focused on enhanced treatment adherenceand reduced alcohol consumption.

E122. The use according to embodiment 121, wherein said counseling isperformed according to the BRENDA model.

E123. The use according to any of embodiments 91-122, wherein saidpatient is a patient for whom immediate abstinence is not a treatmentgoal.

E124. The use according to any of embodiments 91-123, wherein saidmedicament is to be used for a treatment period of 6 -12 months such as6 months.

E125. The use according to any of embodiments 91-124, wherein saidpatient is an adult or an adolescent.

E126. The use according to any of embodiments 91-125, wherein saidpatient is 12 years or older, such as 14 years or older, such as 16years or older, such as 18 years or older.

E127. The use according to any of embodiments 91-126, wherein saidmedicament comprises nalmefene in a dose of 10-20 mg such as 10 mg, 11mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg.

E128. The use according to embodiment 127, wherein said medicamentcomprises nalmefene in a dose of 18 mg.

E129. The use according to any of embodiments 91-128, wherein saidmedicament comprises nalmefene in the form of a pharmaceuticallyacceptable acid addition salt.

E130. The use according to embodiment 129, wherein said medicamentcomprises nalmefene in the form the hydrochloride salt.

E131. The use according to embodiment 130, wherein said medicamentcomprises nalmefene in the form the hydrochloride dihydrate.

E132. The use according to any of embodiments 91-131, wherein said saidmedicament comprises nalmefene in a crystalline form.

E133. The use according to any of embodiments 91-132, wherein saidmedicament comprises an oral dose form such as tablets or capsules.

E134. The use according to any of embodiments 91-133, wherein saidmedicament comprises a further active ingredient.

E135. The use according to any of embodiments 91-134, wherein saidpatient does not fall into one or more of the following categories:patients taking opioid analgesics, opioid-addicted patients withoutsuccessful withdrawal, patients with acute symptoms of opioidwithdrawal, patients for whom recent use of opioids is suspected,patients with moderate or severe hepatic impairment, patients withmoderate or severe renal impairment, patients with current or recentopioid addiction, patients with a recent history of acute alcoholwithdrawal syndrome (including hallucinations, seizures, and deliriumtremens).

EXAMPLES

The invention will be illustrated by the following non-limitingexamples.

The efficacy of nalmefene on the reduction of alcohol consumption inpatients with alcohol dependence (DSM-IV) was evaluated in two efficacystudies (Study 12014A and Study 12023A). Both studies were randomised,double blind, two-parallel group, placebo controlled, and after 6 monthsof treatment, patients receiving nalmefene were re-randomised to receiveeither placebo or nalmefene in a 1 month run out period. The efficacy ofnalmefene was also evaluated in a randomised, double blind, two parallelgroup, placebo controlled 1 year safety study (Study 12013A). Thestudies included 1941 patients, 1144 of whom were treated with nalmefene18 mg in an as-needed dosing regimen.

The studies were conducted applying an outpatient setting withoutpreceding detoxification. Higher CIWA withdrawal scores (ClinicalInstitute Withdrawal Assessment for Alcohol) at screening as well as ahistory of delirium tremens and seizures would be indicative for thenecessity of prior inpatient detoxification. Patients with abuse ofsubstance other than alcohol and subjects with significant depressive orpsychotic co-morbidity were excluded.

The studies included outpatients, aged ≧18 years, with a primarydiagnosis of alcohol dependence. A patient was eligible forparticipation in the study if, in the 4 weeks preceding the ScreeningVisit (Baseline period), he/she had >6 HDDs, at least a medium DRL(calculated as mean daily alcohol consumption in g/day i.e. >40 g/dayfor men and >20 g/day for women calculated as mean daily alcoholconsumption over the 4 week period preceding the screening visit), and≦14 consecutive abstinent days. The timeline followback (TLFB) methodwas used to obtain estimates of the patient's daily drinking.

The studies were conducted over a 34 week period (12 visits) in totaland consisted of four sequential periods: a 2-week screening period, a24-week double-blind treatment period, a 4-week double-blindplacebo-controlled run-out in each of the treatment arms and finally a4-week safety follow-up. One to two weeks after the Screening Visit thepatients were randomised 1:1 to 24 weeks of as-needed, double-blindtreatment (Main Treatment Period; MTP) with nalmefene (18 mg) orplacebo. The patients who completed 24 weeks of double-blind treatmententered a 4-week, double-blind Run-out Period (ROP). The patientsrandomised to nalmefene were re-randomised 1:1 to receive nalmefene (18mg, as-needed) or placebo and the patients randomised to placebocontinued on placebo.

The Timeline Follow-back (TLFB) method was used to collect se reporteddrinking data (alcohol consumption).

At the initial visit, the patients' clinical status, social situation,and alcohol consumption pattern were evaluated (based on patientreporting). After a 1- to 2week observation period the drinking risklevel was re-assessed (i.e. the mean daily alcohol consumption over the1-2 week assessment period was calculated), and treatment with nalmefenewas initiated together with counseling with focus on motivating thepatients to adhere to the treatment and to change their drinkingbehavior. In all the studies, a motivational and adherence enhancingintervention, according to the BRENDA model, was administered to all thepatients to support the patients in changing their behavior and toenhance adherence to treatment.

The patients' alcohol intake (g/day) was estimated based on nationaldefinitions of standard units (subsequently converted into grams ofalcohol). To define the standard units, a standard drink conversion cardwas distributed to each patient at the Screening Visit. Each patient wasalso provided with a calendar that he/she could use to support his/herinput to the TLFB, or he/she could use a personal calendar, ifpreferred. For all the variables derived from the TLFB data, baselinewas defined as the month (that is, 4 weeks /28 consecutive days)preceding the Screening Visit. The investigational medicinal product(IMP) was taken as-needed. Each patient was instructed to take a maximumof one tablet on each day the patient perceived a risk of drinkingalcohol, preferably 1 to 2 hours prior to the anticipated time ofdrinking. If the patient had started drinking alcohol without takingnalmefene, the patient as to take one tablet as soon as possible. Thedates when nalmefene was taken/not taken were recorded using the TLFBmethod. The chosen comparator was placebo

The demographic data for each study are provided in tables 2-4 below.Table 5 summarizes the number of patients in the efficacy analysis foreach patient group.

TABLE 2 Patient Demographics (APRS)—Study 12014A Placebo Nalmefene TotalNumber of Patients 298 306 604 Age (years) N 298 306 604 MEAN 52.1251.02 51.56 STD 9.08 10.12 9.63 MIN 24.00 24.00 24.00 MAX 75.00 72.0075.00 MEDIAN 52.00 51.00 52.00 Age group <25  1 (0.3)  1 (0.3)  2 (0.3)(years) n (%) >=25 and  6 (2.0) 14 (4.6) 20 (3.3) <35 >=35 and  54(18.1)  65 (21.2) 119 (19.7) <45 >=45 and 115 (38.6) 108 (35.3) 223(36.9) <55 >=55 and  97 (32.6)  87 (28.4) 184 (30.5) <55 >=65 25 (8.4) 31 (10.1) 56 (9.3) Sex n (%) F  96 (32.2) 102 (33.3) 198 (32.8) M 202(67.8) 204 (66.7) 406 (67.2) Race n (%) BLACK  1 (0.3)  1 (0.2)CAUCASIAN 297 (99.7) 306 (100)  603 (99.8)

TABLE 3 Patient Demographics (APRS) - Study 12023A Placebo NalmefeneTotal Number of Patients 360 358 718 Age (years) N 360 358 718 MEAN44.41 45.10 44.75 STD 10.66 10.69 10.67 MIN 20.00 20.00 20.00 MAX 69.0072.00 72.00 MEDIAN 45.00 45.00 45.00 Age group <25  7 (1.9)  9 (2.5) 16(2.2) (years) n (%) >=25 and  69 (19.2)  57 (15.9) 126 (17.5) <35 >=35and  99 (27.5) 106 (29.6) 205 (28.6) <45 >=45 and 123 (34.2) 116 (32.4)239 (33.3) <55 >=55 and  52 (14.4)  57 (15.9) 109 (15.2) <65 >=65 10(2.8) 13 (3.6) 23 (3.2) Sex n (%) F 104 (28.9)  92 (25.7) 196 (27.3) M256 (71.1) 266 (74.3) 522 (72.7) Race n (%) ASIAN  2 (0.6)  2 (0.3)BLACK  2 (0.6)  3 (0.8)  5 (0.7) CAUCASIAN 357 (99.2) 353 (98.6) 710(98.9) OTHER  1 (0.3)  1 (0.1)

TABLE 4 Patient Demographics (APRS) - Study 12013A Placebo NalmefeneTotal Number of Patients 166 509 675 Age (years) N 166 509 675 MEAN44.27 44.26 44.26 STD 11.99 11.24 11.42 MIN 18.00 19.00 18.00 MAX 72.0077.00 77.00 MEDIAN 44.00 44.00 44.00 Age group <25  8 (4.8) 14 (2.8) 22(3.3) (years) n (%) >=25 and  30 (18.1)  91 (17.9) 121 (17.9) <35 >=35and  47 (28.3) 160 (31.4) 207 (30.7) <45 >=45 and  44 (26.5) 153 (30.1)197 (29.2) <55 >=55 and  30 (18.1)  64 (12.6)  94 (13.9) <65 >=65  7(4.2) 27 (5.3) 34 (5.0) Sex n (%) F  39 (23.5) 116 (22.8) 155 (23.0) M127 (76.5) 393 (77.2) 520 (77.0) Race n (%) ASIAN  1 (0.2)  1 (0.1)BLACK  1 (0.2)  1 (0.1) CAUCASIAN 165 (99.4) 506 (99.4) 671 (99.4) OTHER 1 (0.6)  1 (0.2)  2 (0.3)

TABLE 5 Number of patients in efficacy analysis Study Population PlaceboNalmefene 12014A Total population 289 290 High DRL at baseline 230 222Total excl. ERs 231 246 High DRL at baseline & 167 171 randomisation12023A Total population 326 329 High DRL at baseline 247 265 Total excl.ERs 221 216 High DRL at baseline & 155 148 randomisation 12013A Totalpopulation 137 415 High DRL at baseline 88 252 Total excl. ERs 79 258High DRL at baseline & 42 141 randomisation

The efficacy of nalmefene was measured using two co-primary endpoints:the change in the monthly number of heavy drinking days (HDDs) and thechange in the mean daily total alcohol consumption (TAC) per month (=28days). A HDD was defined as a day with a consumption ≧60 g alcohol formen and a ≧40 g for women. Data obtained at month 6 are listed in Table6 below. The change in HDD and TAC over time in patients treated withnalmefene or placebo is further-more reflected in FIGS. 1-12.

TABLE 6 Results (Mixed model repeated measures (MMRM) analysis) at Month6. Mean difference to placebo in the change from End- baseline to Studypoint Population month 6 p-value 12014A HDD Total population −2.3days/month 0.002 High DRL at baseline −2.6 days/month 0.006 Total excl.ERs −3.1 days/month <0.001 High DRL at baseline & −3.7 days/month 0.001randomisation TAC Total population −11.0 g/day <0.001 High DRL atbaseline −12.2 g/day <0.001 Total excl. ERs −14.5 g/day <0.001 High DRLat baseline & −18.3 g/day <0.001 randomisation 12023A HDD Totalpopulation −1.7 days/month 0.012 High DRL at baseline −2 1 days/month0.010 Total excl. ERs −2.0 days/month 0.012 High DRL at baseline & −2.7days/month 0.025 randomisation TAC Total population −5.0 g/day 0.088High DRL at baseline −6.6 g/day 0.062 Total excl. ERs −7.0 g/day 0.037High DRL at baseline & −10.3 g/day 0.040 randomisation 12013A HDD Totalpopulation −0.9 days/month 0.160 High DRL at baseline −1.1 days/month0.253 Total excl. ERs −1.4 days/month 0.082 High DRL at baseline & −2.6days/month 0.071 randomisation TAC Total population −3.5 g/day 0.232High DRL at baseline −5.6 g/day 0.219 Total excl. ERs −7.9 g/day 0.036High DRL at baseline & −15.3 g/day 0.031 randomisation

Table 6 indicates that in all three studies the difference betweennalmefene and placebo measured in HDDs and TAC was more pronounced inthe group of patients with High DRL at baseline than in the total studypopulation.

Table 6 also indicates that in all three studies the difference betweennalmefene and placebo measured in HDDs and TAC was more pronounced inthe group of patients excluding ERs than in the total study population.

Finally, table 6 clearly indicates that in all three studies thedifference between nalmefene and placebo measured in HDDs and TAC wasmore pronounced in the group of patients with High DRL at baseline andrandomization than in the total study population.

1. A method of reducing alcohol consumption in a patient wherein said method comprises the following steps: a identifying a patient i) who has a high DRL, and ii) who maintains a high DRL after an observation period following initial assessment, and b) administering a therapeutically effective amount of nalmefene to the patient identified in step a), wherein said nalmefene is to be administered as-needed about 1-2 hours prior to the anticipated time of drinking.
 2. The method according to claim 1, wherein said observation period following initial assessment is about 1-2 weeks.
 3. The method according to claim 1, wherein the patient identified in step a) has a DRL corresponding to consumption ≧60 g/day of pure alcohol for men and ≧40 g/day for women.
 4. The method according to claim 1, wherein said high URL in identified in step a) i) has been assessed by calculating mean daily alcohol consumption in g/day over a period preceding assessment, wherein said period is 1 week or longer.
 5. The method according to claim 1, wherein said maintained DRL in step a) ii) is assessed by calculating mean daily alcohol consumption in g/day over said observation period.
 6. The method according to claim 1, wherein said patient is subject to counseling focused on enhanced treatment adherence and reduced alcohol consumption.
 7. The method according to claim 6, wherein said counseling is performed according to the BRENDA model.
 8. The method according to claim 1, wherein said nalmefene is to be used for a treatment period of 6-12 months.
 9. The method according to claim 1, wherein said patient is 12 years or older.
 10. The method according to claim 1-9, wherein the amount of nalmefene is 10-20 mg.
 11. The method according to any of claim 1, wherein said nalmefene is administered in the form of a pharmaceutically acceptable acid addition salt.
 12. The method according to claim 11, wherein said nalmefene is administered in the form of the hydrochloride dihydrate.
 13. The method according to claim 1, wherein said nalmefene is administered in an oral dose for that is tablets or capsules.
 14. The method according to claim 1, wherein said nalmefene is administered in combination with a further active ingredient
 15. The method according to claim 1, wherein said patient has an alcohol use disorder.
 16. The method according to claim 1, wherein said patient has alcohol dependence. 